Figure 1.

Mechanisms of membrane trafficking for G-protein-coupled receptors (GPCRs). Upon agonist
binding (1), a GPCR, including the delta-opioid receptor (DOR), is phosphorylated by GPCR kinases
(GRK) (2), binds to proteins AP-2 and arrestin (3), and undergoes the process of internalization via endocytosis through clathrin-coated
pit (4). Once internalized, the receptor is subjected to highly regulated sorting processes
and is targeted either to endosomes in the recycling pathway (5) for membrane insertion, or to lysosomes for degradation through the degradation
pathway (6). DOR is synthesized in the endoplasmic reticulum (ER) (7), then transported to the trans-Golgi network (8) through ER-Golgi complex, and becomes a mature receptor. Matured DOR is normally
targeted intracellularly in large dense-core vesicles (9) as intracellular pool of DOR ready for membrane trafficking and insertion. Chronic
pain conditions induce the release of a number of inflammatory mediators, which activate
corresponding receptors (10) and increase intracellular calcium concentration, causing the membrane trafficking
of DOR. Persistent stimulation of mu-opioid receptors (MOR) by chronic opioids (11) can induce the membrane trafficking of intracellular DOR and bring out functional
DOR through yet unknown mechanisms.